CO-CRYSTAL OF KETOPROFEN, LYSINE AND GABAPENTIN, PHARMACEUTICAL COMPOSITIONS AND THEIR MEDICAL USE

Abstract

The present invention relates to a new co-crystal of Ketoprofen, Lysine and Gabapentin, to pharmaceutical compositions and to their use in the prevention, reduction or treatment of pain and/or inflammation.

Claims

1-16. (canceled)

17. A co-crystal of Ketoprofen, Lysine and Gabapentin, wherein the molar ratio of the components is 1:1:2.

18. The co-crystal according to claim 17, characterized by the following XRPD diffraction peaks: 3.6, 6.3, 18.6 and 21.7 degrees 2-theta±0.2 degrees 2-theta.

19. The co-crystal according to claim 18, further characterized by the following XRPD diffraction peaks: 9.6, 17.2 and 20.5 degrees 2-theta±0.2 degrees 2-theta.

20. The co-crystal according to claim 17, further characterized by one or more of the following: a DSC thermogram with the endothermic peak corresponding to the melting point at about 143.5° C. as shown in FIG. 3, solution .sup.1H-NMR signals shown in FIG. 7, and solid state .sup.13C CPMAS signals as shown in FIG. 8.

21. The co-crystal according to claim 17, wherein the Ketoprofen is (S)-Ketoprofen and/or the Lysine is (S)-Lysine.

22. A method for the prevention, reduction or treatment of pain and/or inflammation in a subject in need thereof, comprising administration of the co-crystal according to claim 17, alone or in combination with one or more pharmaceutically acceptable excipients.

23. The method according to claim 22, wherein the pain is acute or chronic pain.

24. The method according to claim 22, wherein the pain is selected from headache, toothache, menstrual pain, muscle pain, neuropathic pain, pain associated to neuroinflammation, diabetic neuropathy, cancer pain, osteoarthritis, low back pain, sciatalgia, fibromyalgia. trigeminal neuralgia; post-surgical and post-operative pain, post herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain.

25. A pharmaceutical composition comprising the co-crystal according to claim 17 and a least one pharmaceutically acceptable excipient.

26. The pharmaceutical composition according to claim 25, which contains 0.5-60% by weight of the co-crystal and 40-99.5% by weight of one or more pharmaceutically acceptable excipients.

27. The pharmaceutical composition according to claim 25, which is a solid composition for oral administration.

28. The pharmaceutical composition according to claim 26, which is a solid composition for oral administration.

29. A process for the preparation of the co-crystal according to claim 17, which comprises: a) suspending Ketoprofen, Lysine and Gabapentin, in a molar ratio of 1/1 to 1.5/2 to 2.5, in a suitable solvent, b) dissolving Ketoprofen, Lysine and Gabapentin, optionally by heating the suspension and/or under stirring, till a clear solution is obtained c) subsequently cooling the solution, and d) optionally adding an anti-solvent.

30. The process according to claim 29, wherein the Ketoprofen and Lysine in step a) are in form of a Ketoprofen Lysine salt or a co-crystal.

31. The process according to claim 29, wherein the Ketoprofen is the free acid and/or the Lysine is in neutral form.

32. The process according to claim 29, wherein the Gabapentin is in neutral form (zwitterionic internal salt).

33. The process according to claim 2 wherein in step a) the molar ratio of Gabapentin vs Ketoprofen is between 2:1 and 2.2:1.

34. The process according to claim 33, wherein in step a) the molar ratio of Gabapentin vs Ketoprofen is about 2:1.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0056] FIG. 1: Powder X-Ray diffraction pattern of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal

[0057] FIG. 2: Powder X-Ray diffraction patterns of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal and 1:1:1 Ketoprofen-Lysine-Gabapentin co-crystal

[0058] FIG. 3: DSC thermogram of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal

[0059] FIG. 4: DSC thermogram of 1:1:1 Ketoprofen-Lysine-Gabapentin co-crystal

[0060] FIG. 5: DSC thermogram of Ketoprofen Lysine co-crystal Form I

[0061] FIG. 6: DSC thermogram of Gabapentin

[0062] FIG. 7: .sup.1H-NMR spectrum (400 MHz, D.sub.2O) of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal.

[0063] FIG. 8: .sup.13C-CPMAS ss-NMR of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal.

[0064] Keys in the Figures: K-L-GAB Co-xx Ketoprofen Lysine Gabapentin co-crystal.

DETAILED DESCRIPTION OF THE INVENTION

[0065] An object of the present invention is a co-crystal of Ketoprofen, Lysine and Gabapentin wherein the molar ratio of the components is 1:1:2.

[0066] In line with the solid state .sup.13C-NMR analysis reported in the experimental part, in the present co-crystal Ketoprofen carboxylic group is deprotonated and interacts with protonated Lysine ε-NH.sub.3+ group through ionic bonds forming a neutral salt. The Ketoprofen Lysine neutral salt interacts with two molecules of Gabapentin through non-ionic bonds.

[0067] The co-crystal of the present invention is further characterized by the following XRPD diffraction peaks: 3.6, 6.3, 18.6 and 21.7 degrees 2-theta±0.2 degrees 2-theta, with a margin of error on the value indicated for each peak of ±0.2 degrees 2-theta, preferably further characterized by the following XRPD diffraction peaks: 9.6, 17.2 and 20.5 degrees 2-theta±0.2 degrees 2-theta, as shown in FIG. 1 and in Table 2.

[0068] This crystalline form of the co-crystal of the invention is herein named Form I.

[0069] Other polymorphs of the present co-crystal are also within the scope of the invention.

[0070] The co-crystal of the present invention is further characterized by the DSC thermogram of FIG. 3, with the endothermic sharp peak of the co-crystal corresponding to the melting point at 143.5° C. with an onset at 139.6° C., by solution .sup.1H-NMR spectrum of FIG. 7 and relative assignments in Table 4 and solid state .sup.13C CPMAS of FIG. 8 and relative assignments in Table 5.

[0071] In the co-crystal of the invention, Ketoprofen can be racemic (S,R) Ketoprofen, (S)-Ketoprofen or (R)-Ketoprofen or any admixture thereof.

[0072] In one embodiment Ketoprofen is (S)-Ketoprofen (also named DexKetoprofen).

[0073] In another embodiment Ketoprofen is (R)-Ketoprofen.

[0074] In the co-crystal of the invention, Lysine can be racemic (S,R) Lysine, (S) Lysine or (R) Lysine, or any admixture thereof, preferably is the natural aminoacid (S)-Lysine also named L-Lysine.

[0075] In one embodiment, the co-crystal of the invention comprises (S)-Ketoprofen.

[0076] In one embodiment, the co-crystal of the invention comprises (S)-Lysine.

[0077] In one embodiment, the co-crystal of the invention comprises (S)-Ketoprofen and (S)-Lysine.

[0078] The co-crystal of the present invention can exist in unsolvated forms as well solvated forms, including hydrated forms.

[0079] The co-crystal of the present invention is easily obtainable and stable.

[0080] The co-crystal of the present invention can show improved pharmaceutical properties, pharmacokinetics and efficacy in pain conditions, especially when compared to Gabapentin or Ketoprofen alone and even when compared to their admixture.

[0081] A further object of the present invention is a process for the preparation of the co-crystal of the invention, which comprises: [0082] a) suspending Ketoprofen, Lysine and Gabapentin, in a molar ratio of 1/1 to 1.5/2 to 2.5, in a suitable solvent, [0083] b) dissolving Ketoprofen, Lysine and Gabapentin, optionally by heating the suspension and/or under stirring, till a clear solution is obtained [0084] c) subsequently cooling the solution, and [0085] d) optionally adding an anti-solvent.

[0086] In the present process, the starting material for Ketoprofen can be Ketoprofen free acid or a Ketoprofen salt, preferably Ketoprofen Lysinate, or any Ketoprofen Lysine co-crystal. In case of Ketoprofen free add or a Ketoprofen salt different from the Lysinate, Lysine is added, preferably in its neutral form. Lysine is preferably used in the same molar amount of Ketoprofen.

[0087] Ketoprofen and Lysine can be in any optical form, namely as any pure optical Isomer or in any admixture of optical isomers, including racemates.

[0088] In step a) of the present process, the molar ratio of Gabapentin vs Ketoprofen is preferably between 2:1 and 2.5:1, more preferably between 2:1 and 2.2:1, even more preferably is about 2:1.

[0089] In one embodiment, the molar ratio of Ketoprofen Lysine Gabapentin in step a) is about 1:1:2.

[0090] In the present process, suitable solvents are alcohols, preferably methanol and ethanol, esters, preferably ethyl acetate, ethers, preferably tetrahydrofuran and tert-butylmethyl ether or aromatic solvents, preferably toluene.

[0091] Preferably, step b) is performed under heating at the temperature of reflux of the solvent.

[0092] Preferably, the solution from step b) is cooled at room temperature.

[0093] Preferably the solution from step b) is cooled at room temperature and filtered

[0094] Preferably, the precipitation of the co-crystal is favored by addition of an anti-solvent.

[0095] The present process provides the co-crystal of the invention with high yields. It is simple and easy scalable at industrial level.

[0096] According to one embodiment, in step a) of the process according to the invention, Ketoprofen and Lysine may be present as a pre-formed salt or co-crystal, in any polymorphic form.

[0097] The starting material for the manufacture of the co-crystal of the present invention is Gabapentin, Ketoprofen and Ketoprofen Lysine salt or co-crystals may be prepared in accordance with methods of synthesis previously published and well known to the organic chemist of ordinary skill.

[0098] Ketoprofen Lysine salt can be prepared as described for instance in GB1497044A and BE882889.

[0099] Ketoprofen Lysine co-crystal Form I can be prepared as described for instance in the European Patent Application n. EP18215336.1 or in the International Patent Application PCT/IEP2019/025464.

[0100] Ketoprofen Lysine co-crystal Form IV can be prepared as described for instance n EP19219293.8.

[0101] According to an alternative embodiment, said Ketoprofen is a free acid and/or said Lysine is in neutral form.

[0102] In the present preparation process, Gabapentin is preferably used in its neutral form (zwitterionic internal salt) or in any acid or basic salified form, for instance as Gabapentin hydrochloride or Gabapentin Sodium salt.

[0103] Preferably, Gabapentin is used in its neutral form.

[0104] Gabapentin can be in any polymorph form.

[0105] The present invention furthermore relates to a pharmaceutical composition comprising the co-crystal of Ketoprofen-Lysine-Gabapentin according to the present invention, in particular the co-crystal of Ketoprofen-Lysine-Gabapentin as defined above and a least one pharmaceutically acceptable excipient.

[0106] For instance, the composition according to the present invention may contain 0.5-60% by weight of the co-crystal as defined herein and 40-99.5% by weight of one or more pharmaceutically acceptable excipients.

[0107] The choice of the excipients will to a large extent depend on factors such as the particular mode of administration, the effect on solubility and stability, and the nature of the dosage form.

[0108] Pharmaceutical compositions according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.

[0109] The pharmaceutical composition of the present invention preferably is an oral solid composition, such as for instance a capsule, pellet, tablet, cachet, chewable dosage forms, powder: lozenge, granules, oral soluble granulate, suspension, emulsion, spray, or as dry powdered form to be reconstituted with a liquid medium

[0110] The pharmaceutical composition can additionally contain one or more pharmaceutically acceptable excipients, such as fillers, binders, glidants, disintegrants, flow regulating agents and release agents.

[0111] Suitable excipients are for example disclosed in “Handbook of Pharmaceutical Excipients”, 3rd Edition, published by A.H. Kibbe, American Pharmaceutical Association, Washington, U.S.A., and Pharmaceutical Press, London.

[0112] Suitable fillers are for example lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dibasic calcium phosphate dihydrate and calcium hydrogen phosphate.

[0113] Fillers can be present in an amount of 0-80% by weight, preferably in an amount of 10-60% by weight of the total weight of the composition.

[0114] Suitable binders are for example polyvinylpyrrolidone, microcrystalline cellulose hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sugars, dextran, cornstarch, gelatin, polyethylene glycol, natural and synthetic gums, pregelatinised starch.

[0115] Binders can be present in an amount of 0-80% by weight, preferably in an amount of 10-60% by weight of the total weight of the composition.

[0116] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable glidants are for example alkaline earth metal salts of fatty acids, like stearic acid such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.

[0117] The glidant can be present for example in an amount of 0-2% by weight, preferably in an amount of 0.5-1.5% by weight of the total weight of the composition.

[0118] Suitable disintegrants are for example croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crosspovidone), sodium carboxymethylglycolate, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch, sodium alginate and sodium bicarbonate.

[0119] The disintegrant can be present in an amount of 0-20% by weight, preferably in an amount of 1-15% by weight of the total weight of the composition.

[0120] A suitable flow-regulating agent is for example colloidal silica. The flow regulating agent can be present in an amount of 0-8% by weight, preferably in an amount of 0.1-3% by weight of the total weight of this composition.

[0121] A suitable release agent is for example talcum. The release agent can be present in an amount of 0-5% by weight, preferably in an amount of 0.5-3% by weight of the total weight of the composition.

[0122] The solid composition may be coated, preferably film coated.

[0123] Suitable coating agents are for example cellulose derivatives, poly(meth)acrylate, polyvinyl pyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.

[0124] There are many situations in which it will be advantageous or even necessary to deliver the co-crystal of the present invention as a solid, for instance by installing a solid implant composition into suitable body tissues or cavities.

[0125] The implant may comprise a matrix of bio-compatible and bioerodible materials in which particles of the co-crystal of the present invention are dispersed, or in which, possibly, globules or isolated cells of a liquid mixture of the present co-crystal are entrapped. Desirably, the matrix will be broken down and completely absorbed by the body. The composition of the matrix is also preferably selected to provide controlled-, sustained-, and/or delayed release of the co-crystal of the present invention over extended periods.

[0126] Alternatively, the co-crystal of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.

[0127] The present composition can be administered topically to the skin or mucosa, that is dermally, epidermally, subepidermally or transdermally.

[0128] The present composition can be administered sublingually or via a suppository.

[0129] Typical formulations for this purpose include pour-on, spot-on, dip, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, depots, sponges, fibres, bandages, microemulsions, orosoluble granulates. Liposomes may also be used.

[0130] The pharmaceutical composition of the present invention may be a solid composition for the extemporaneous preparation of a solution for oral or parenteral administration, to be administered for example by intramuscular, intrapentoneal, or intravenous injection.

[0131] The pharmaceutical composition of the present invention can be prepared by methods well known to a person skilled in the art.

[0132] The composition of the invention may be of immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release type.

[0133] According to a further embodiment, the pharmaceutical composition of the invention may comprise the co-crystal of the invention and at least another pharmaceutically active ingredient.

[0134] The other pharmaceutically active ingredient will be determined by the circumstances under which the therapeutic agent of the present invention is administered.

[0135] A further object of the present invention is the co-crystal of the invention for use as a medicament.

[0136] The medical use can be curative, prophylactic or palliative.

[0137] The association of the two active ingredients in the same crystal can exhibit several advantages for the present medical use

[0138] First, Gabapentin and Ketoprofen Lysine being linked in the co-crystal, often behave as a single chemical entity, thus facilitating the treatments, formulation, dosage etc.

[0139] Furthermore the two active ingredients are complementing each other in the treatment especially of pain, but possibly also of various other diseases or symptoms.

[0140] Another advantage is that the association of two active ingredients into one unique species may allow for a better Pharmacokinetic/Pharmacodynamic (PKPD) including also a better penetration of the blood-brain barrier, which helps in the treatment of pain.

[0141] The co-crystal and the composition of the present invention can show a synergistic activity of the active ingredients Gabapentin and Ketoprofen Lysine.

[0142] This synergy provides can provide enhanced clinical efficacy compared to the individual components of the co-crystal when administered separately, or a reduction in the required dose of each compound, leading to a reduction in side effects whilst maintaining or enhancing the clinical effectiveness of the compounds and treatment.

[0143] For example, the patient may experience an improved reduction in the frequency and severity of pain and/or inflammation. Furthermore, the patient may benefit from a longer duration of action from the co-crystal treatment than from treatment with Gabapentin or with Ketoprofen Lysine or with their combination.

[0144] It is necessary for the skilled artisan, such as a physician or a veterinarian, not only to determine the preferred route of administration and the corresponding dosage form and amount, but said artisan must also determine the dosing regimen.

[0145] The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.

[0146] The daily dosage of the co-crystal according to the invention for humans preferably provides for Ketoprofen acid form in an amount between 25 and 200 mg, preferably between 25 and 100 mg, more preferably of about 50 mg, from 1 to 6 times per day, preferably from 1 to 4 times a day, resulting the total Gabapentin amount very low if compared to the normal dosage of Gabapentin alone.

[0147] A further object of the present invention is the co-crystal of the invention for use in the treatment of pain and/or inflammation.

[0148] The co-crystal and the composition of the present invention are preferably used for the treatment of pain, preferably of acute or chronic pain and inflammation, preferably neuroinflammation.

[0149] Preferably, said pain is selected from headache, toothache, menstrual pain, muscle pain, neuropathic pain, diabetic, neuropathy, pain associated to neuroinflammation, cancer pain, osteoarthritis, low back pain, sciatalgia, fibromyalgia, trigeminal neuralgia; post-surgical and post-operative pain, post herpetic neuralgia, rheumatoid arthritis, ankylosing spondylitis, frozen shoulder, phantom limb pain or HIV pain.

[0150] A further object of the present invention is a method for the treatment of pain and/or inflammation comprising administering to a patient an effective amount of the co-crystal of the invention.

EXPERIMENTAL PART

[0151] In the following, the manufacture of the co-crystal of Ketoprofen, Lysine and Gabapentin, its analytical and biological characterization are described

1. Synthesis of the 1:1:2 Ketoprofen-Lysine-Gabapentin Co-Crystal

[0152] Ketoprofen Lysine co-crystal Form I (3.0 g, 1.0 eq.), prepared as described in the European Patent Application n. EP18215336.1 or in the International Patent Application PCT/EP2019/025464 and Gabapentin (2.56 g, 2.0 eq.) were dissolved in 60 ml of boiling methanol. The clear solution was allowed to cool at room temperature, polish-filtered (0.45 pm HPLC filter) and then added to 240 ml of THF under stirring. The solid precipitation took place in approximatively 45 minutes and the suspension was stirred at 25° C. for 2 hours (300 rpm), The solid product was isolated by vacuum filtration on a paper filter, washed with methanol (2×3 ml) and then squeezed under a nitrogen flow for approximatively 10 minutes. The solid was gently ground and then dried at 40° C and 30 mbar overnight affording 4.8 grams of the desired product as a white solid (Yield: 86%).

2. XRPD Analysis

[0153] The XRPD analysis was carried out with the following instrument and under the conditions reported in Table 1 below:

TABLE-US-00001 TABLE 1 Instrument type: Rigaku MiniFlex600 Application SW: Miniflex Guidance Measurement Details Measurement type: Single scan Sample mode: Reflection Scan Scan range: 3.000-40.000° (2θ) Step size: 0.01° (2θ) Speed: 10.0°/min (2θ) Scan mode: Continuous Used wavelength Intended wavelength type: Ka1 Kα1: 1.540598 Å Kα2: 1.544426 Å Kα2/Kα1 intensity ratio: 0.50 Kα: 1.541874 Å Kα: 1.392250 Å Instrument Details X-Ray Generator Tube output voltage: 40 kV Tube output: 15 mA High-voltage generation High-frequency Cockcroft-Walton method method: Stability: Within ±0.05% for both the tube voltage and tube current, with reference to ±10% of input power variation. X-ray tube Name: Toshiba Analix type A-26L Anode material: Cu Maximus output: 0.60 kW Focus size: 1 × 10 mm Kβ Filter Name: Ni-filter Thickness (mm): 0.015 Material: Ni Goniometer (Angle measuring device) Type: Vertical θ/2θ Goniometer radius: 150 mm Scanning axis: θ/2θ linked 2θ scanning range: +2° to +140° θ/2θ axis minimum step 0.005° (2θ) angle: Position speed: 500°/min (2θ) Scanning speed: 0.01 to 100°/min Datum angle: 2θ = 10° X-ray take-off angle: 6° (fixed) Slit DS: 1.25° IHS: 10.0 mm SS: none (open) RS: none (open) Incident side Soller slit:  2.5° Receiving side Soller slit:  2.5° Detector Name: D/tex Ultra High-speed 1D Detector Window material: Be Effective window size: 13 mm (H) × 20 mm (W) Dimensions: 80 mm (L)

[0154] The Powder X-Ray diffractogram of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal is reported in FIG. 1. A comparison between the Powder X-Ray diffractograms of Ketoprofen-Lysine-Gabapentin co-crystals 1:1:1 and 1:1:2 is reported in FIG. 2.

[0155] The XRPD peak list of the 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal is reported in Table 2 below:

TABLE-US-00002 TABLE 2 XRPD Peak Least 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal Pos. [°2Th.] Height [cts] FWHM [°2Th.] d-spacing [Å] | Rel. Int. [%] 3.6251 11156.56 0.0984 3.04710 100.00 6.2531 5100.16 0.3542 2.96523 45.71 9.5963 2389.96 0.3149 2.17056 21.42 10.2396 71.53 0.2574 4.99385 0.64 12.6123 720.19 0.1362 4.79862 6.46 15.8941 741.78 0.3442 4.43123 6.65 17.1933 961.40 0.1481 4.22708 8.62 17.2258 742.52 0.1755 4.07409 6.66 18.6398 2923.12 0.4700 3.67121 26.20 20.4830 1912.02 0.3149 3.51106 17.14 21.6611 4299.12 0.3287 3.18062 38.53 21.9123 621.98 0.2123 3.30203 5.58 24.5267 913.23 0.2311 3.16223 8.19 24.8963 617.47 0.0984 3.04704 5.53 25.0002 615.02 0.3542 2.96564 5.51 26.3078 45.19 0.1782 2.87075 0.41 28.0023 311.23 0.2358 4.99385 2.79 29.2987 105.42 0.5399 3.48072 0.94 30.0023 107.36 0.3002 3.38773 0.96 31.1012 64.31 0.3912 3.16223 0.58

3. Thermal Analyses

DSC Analysis

[0156] The analysis was carried out using the instrument DSC Mettler Toledo DSC1.

[0157] The sample was weighed in an aluminum pan hermetically sealed with an aluminum cover. The analysis was performed by heating the sample from 25° C to 320° C. at 10 K/min, under the conditions shown in Table 3 below:

TABLE-US-00003 TABLE 3 Temperature Data Temperature range −40° C. to 450° C. Temperature accuracy    ±0.2K Temperature precision   ±0.02K Furnace temperature resolution ±0.00006K Heating rate 0.02 to 300K/min Cooling rate 0.02 to 50K/min Cooling time 5 min (100° C. to 0° C.) Calorimetric Data Sensor type FRS5 Sensor material Ceramic Number of thermocouples 56 Signal time constant 1.8 s Indium peak (height to width) 17 TAWN resolution 0.12 Sensitivity 11.9 Resolution 0.04 μW Digital resolution 16.8 million points

[0158] The analysis was carried out on a sample of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal. The DSC thermogram is shown in FIG. 3.

[0159] In FIGS. 4, 5 and 6 the thermograms of 1:1:1 Ketoprofen-Lysine-Gabapentin co-crystal, of Ketoprofen Lysine co-crystal Form I and of Gabapentin are respectively reported.

[0160] The DSC thermogram of FIG. 3 showed a single endothermic event at 143.55° C. (onset 139.57° C.), associated to sample melting and degradation. This peak was clearly different from the endothermic peaks of the thermograms of 1:1:1 Ketoprofen-Lysine-Gabapentin co-crystal, of Ketoprofen Lysine co-crystal Form I and of Gabapentin shown in FIGS. 4 to 6.

4. Liquid and Solid State NMR

[0161] .sup.1H-Nuclear magnetic resonance (NMR) spectra were recorded in the indicated 15 solvent with tetramethylsilane (TMS) as internal standard on a Bruker Avance3 400 MHz instrument. Chemical shifts are reported in parts per million (ppm) relative to the internal standard. Abbreviations are used as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublets of doublet, br=broad. Coupling constants (J values) are given in hertz (Hz).

[0162] The solid-state .sup.13C CPMAS spectra of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal and pure Gabapentin were acquired with a Jeol ECZR 600 instrument, operating at 600.17 and 150.91 MHz, respectively for .sup.1H and .sup.13C nuclei. The powder samples were packed into a cylindrical zirconia rotor with a 3.2 mm o.d. and a 60 μl volume. A sample was collected from each batch and used without further preparations to fill the rotor. The .sup.13C CPMAS spectra were acquired at room temperature, at a spinning speed of 20 kHz, using a ramp cross-polarization pulse sequence with a 90° .sup.1H pulse of 2.1 μs and a contact time of 3.5 ms, An optimized recycle delay of 5.7 (Ketoprofen-Lysine-Gabapentin) or 100 s (GAB) was used, for a number of scans of 2200 (Ketoprofen-Lysine-Gabapentin) or 20 (Gabapentin). For every spectrum, a two-pulse phase modulation (TPPM) decoupling scheme was used, with a radiofrequency field of 108.5 kHz. The .sup.13C chemical shift scale was calibrated through the methylene signal of external standard glycine (at 43.7 ppm). As for the .sup.13C T.sub.1-.sup.1H analysis, 12 spectra were acquired for 350 scans with different relaxation delays, included in the range 0.1-60 s and calculated by the Delta v5.2.1 software through an exponential algorithm, The spectra were acquired at a spinning speed of 20 kHz at room temperature using a ramp cross-polarization pulse sequence with a 90° .sup.1H pulse of 2.1 μs and a contact time of 2 ms.

.SUP.1.H-NMR Spectra of 1:1:2 Ketoprofen-Lysine-Gabapentin Co-Crystal

[0163] .sup.1H-NMR spectrum of Ketoprofen-Lysine-Gabapentin co-crystal confirmed the concomitant presence in the sample of Ketoprofen-Lysine-Gabapentin with 1:1:2 stoichiometry.

[0164] The multiplicity and the assignment of the signals in line with the atoms numbering shown in Scheme 1

##STR00003##

are reported in Table 4 below:

TABLE-US-00004 TABLE 4 .sup.1H-NMR (Ratio KET:LYS:GAB 1:1:2) δ ppm Multiplicity Assignment 7.75-7.78 m, 2H Ar KET 7.69-7.72 m, 2H Ar KET 7.60-7.62 m, 2H Ar KET 7.48-7.56 m, 3H Ar KET 3.71 t, J = 6.4 Hz, 1H CH (2′) LYS 3.69 quart., J = 7.2 Hz, 1H CH (2) KET 2.96 t, J = 7.6 Hz, 2H CH.sub.2 (6′) LYS 2.95 s, 4H CH.sub.2 (9″) GAB 2.36 s, 4H CH.sub.2 (2″) GAB 1.79-1.85 m, 2H CH.sub.2 (5′) LYS 1.62 quint., J = 7.6 Hz, 2H CH.sub.2 (3′) LYS 1.41 d, J = 7.2 Hz, 3H CH3 (3) KET 1.29-1.52 m, 22H CH.sub.2 (4″,5″,6″,7″,8″) GAB; CH.sub.2 (4′) LYS

[0165] The .sup.1H-NMR spectrum (400 MHz, D.sub.2O) of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal is shown in FIG. 7.

Solid State .SUP.13.C CPMAS Spectra of 1:1:2 Ketoprofen-Lysine-Gabapentin Co-Crystal

[0166] A new homogeneous phase of Ketoprofen-Lysine-Gabapentin was confirmed by .sup.13C-CPMAS spectra. The stoichiometry was assessed to be 1:1:2, with one independent molecule of Ketoprofen, Lysine and two of Gabapentin in the unit cell. Ketoprofen carboxylic group is deprotonated and interacts with protonated Lysine ε-NH.sub.3+ group through ionic bonds forming a neutral salt. The Ketoprofen Lysine neutral salt interacts with two molecules of Gabapentin through non-ionic bonds forming a co-crystal. Both Lysine and Gabapentin are in a zwitterionic state in the new crystal form.

[0167] In Table 5 below the characteristic solid-state .sup.13C-NMR resonances are summarized:

TABLE-US-00005 TABLE 5 solid state .sup.13C-NMR .sup.13C δ (ppm) Assignment 194.5 10 181.4  1 178.9  1′ 178.7  1″ 178.1  1″ 145.9 Aromatic C.sub.q 139.6 Aromatic C.sub.q 136.2 Aromatic C.sub.q 135.5 Aromatic CH 132.9 Aromatic CH 131.2 Aromatic CH 130.2 3 Aromatic CH 127.8 2 Aromatic CH 125.2 Aromatic CH 54.1  2′ 49.8  9″ 48.3  2 42.5  6′ 37.1 2″ + 4″ or 8″ 36.8  3′ + 4″ or 8″ 34.6  6″ 30.1  5′ + 3″ 26.1  4′ 25.2  3 23.1 5″ or 7″ 21.1 5″ or 7″

[0168] FIG. 8 displays the CPMAS NMR spectra of 1:1:2 Ketoprofen-Lysine-Gabapentin co-crystal.

[0169] All signals in the spectrum of Ketoprofen-Lysine-Gabapentin co-crystal are characterized by similar .sup.1H T.sub.1 values (around 6.5 s), meaning that spin diffusion is active among the molecules of Ketoprofen, Lysine and Gabapentin, i.e. the four molecules are in the same unit cell.

[0170] Four distinct resonances for carboxylic/carboxylate groups were observed at 181-178 ppm, suggesting a 1:1:2 stoichiometric ratio for the Ketoprofen-Lysine-Gabapentin system.

[0171] The two molecules of Gabapentin are zwitterions: their carboxylate groups are in deprotonated form in 1:1:2 Ketoprofen-Lysine-Gabapentin at 1781 and 178.1 ppm. The zwitterionic carboxylate of Lysine is at 178.9 ppm in 1:1:2 Ketoprofen-Lysine-Gabapentin, due to the involvement of the carboxylate group in strong hydrogen bonds. The Lysine is supposed to be in the zwitterionic form.

[0172] Finally, the carboxylic group of Ketoprofen in 1:1:2 Ketoprofen-Lysine-Gabapentin is at 181.4 ppm.